Side Effects of Invirase (saquinavir)

Invirase (saquinavir) is a type of antiviral medication called a protease inhibitor used to treat infections with the human immunodeficiency virus (HIV).

During infection with HIV, the HIV virus multiplies within the body’s cells. Viruses are released from the cells and spread throughout the body where they infect other cells.

During the production of the viruses, new proteins are made. Some of the proteins are structural proteins, that, is, proteins that form the body of the virus. Other proteins are enzymes which manufacture DNA and other components for the new viruses.

Protease is the enzyme that forms the new structural proteins and enzymes. Invirase blocks the activity of protease and results in the formation of defective viruses that are unable to infect the body's cells. As a result, the number of viruses in the body (the viral load) decreases. Invirase does not prevent the transmission of HIV among individuals, and it does not cure HIV or AIDS. 

Common side effects of Invirase include

• diarrhea,
• nausea,
• vomiting,
• stomach pain,
• tiredness, and
• changes in the shape or location of body fat (especially in the arms, legs, face, neck, breasts, and waist).

Serious side effects of Invirase include

• cough with mucus, chest pain, wheezing, and shortness of breath;
• heart rhythm problems,
• symptoms of high blood sugar (increased thirst, increased urination, dry mouth, fruity breath odor, headache, blurred vision), and
• liver problems (upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, yellowing of the skin or eyes).

Drug interactions of Invirase include triazolam, midazolam, sildenafil, and ergotamine derivatives because Invirase increases the concentration of these drugs in the body and this could cause serious side effects.

Invirase also may inhibit the breakdown of the cholesterol-lowering drugs lovastatin, simvastatin, atorvastatin, and cerivastatin, which may increase the occurrence of muscle breakdown (rhabdomyolysis) which is seen when these drugs accumulate in the body.

Clarithromycin and ketoconazole may increase blood concentrations of Invirase and cause increased severity or frequency of side effects from Invirase.

Invirase also increases the concentration of clarithromycin.

Rifampin and rifabutin decrease blood concentrations of Invirase and may decrease the effectiveness of Invirase.

The combination of Invirase and ritonavir should not be combined with rifampin due to the risk of severe liver damage.

When digoxin is taken by patients receiving Invirase with ritonavir, the amount of digoxin in the body can increase, possibly leading to serious side effects.

Use of Invirase during pregnancy has not been adequately evaluated. It is unknown if Invirase passes into breast milk. HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant.

Invirase can cause serious side effects such as

• Diabetes and high blood sugar. Some people who take protease inhibitors including Invirase get new or more serious diabetes, or high blood sugar.
  • Tell your healthcare provider if you notice an increase in thirst or urinate more often than normal during treatment with Invirase.
• Liver problems. People with liver problems such as Hepatitis B or C, cirrhosis or have a history of alcoholism may have worsening liver problems.
  • Tell your healthcare provider right away if you have any of these signs and symptoms of liver problems:
    • loss of appetite
    • yellowing of your skin or whites of your eyes (jaundice)
    • dark-colored urine
    • pale-colored stools (bowel movements)
    • itchy skin
    • stomach area (abdominal) pain
• Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with protease inhibitors including Invirase.
• Increase in certain fat (cholesterol and triglycerides) levels in your blood. Your healthcare provider will check your blood for high levels of cholesterol and triglycerides before you start Invirase and during treatment with Invirase.
  • Changes in body fat can happen in people who take HIV-1 medicine.
  • These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breasts, and around the middle of your body (trunk).
  • Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time.
  • Tell your healthcare provider if you start having new or worse symptoms of infection after starting your HIV-1 medicine.

The most common side effects of Invirase include

• nausea
• vomiting
• diarrhea
• stomach area (abdominal) pain
• tiredness
• pneumonia
• changes in body fat

These are not all of the possible side effects of Invirase. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Genentech at 1-888-835-2555.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• PR Interval Prolongation
• QT Interval Prolongation

Clinical Trial Experience In Adult Subjects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The original Invirase safety database consisted of a total of 574 adult subjects who received 600 mg of saquinavir mesylate capsules (hard gel) alone or in combination with zidovudine (ZDV) or zalcitabine (ddC).

Combination dosing with ritonavir is based on 352 HIV-1 infected subjects and 166 healthy subjects who received various combinations of either saquinavir mesylate capsules (hard gel or soft gel) with ritonavir.

The recommended dose of Invirase is 1,000 mg twice daily co-administered with ritonavir 100 mg twice daily. Table 1 lists Grade 2, 3 and 4 adverse events that occurred in ≥2% of subjects receiving saquinavir mesylate capsules (soft gel) with ritonavir (1000/100 mg bid).

Table 1 : Grade 2, 3 and 4 Adverse Events (All Causality^a) Reported in ≥2% of Adult Subjects in the MaxCmin 1 Study of Saquinavir Mesylate Capsules (soft gel) in Combination with Ritonavir 1000/100 mg Twice a Day

• Limited experience is available from three trials investigating the pharmacokinetics of the Invirase 500-mg film-coated tablet compared to the 200-mg saquinavir mesylate capsules (hard gel) in healthy volunteers (n=140). In two of these trials, saquinavir was combined with ritonavir; in the other trial, saquinavir was administered as single drug.
• The Invirase tablet and the saquinavir mesylate capsule (hard gel) were similarly tolerated.
• The most common adverse events were gastrointestinal disorders (nausea, vomiting, and diarrhea).
• Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen.
• Thus, similar safety profiles are expected between the two Invirase formulations.

A study investigating the drug-drug interaction of rifampin 600 mg/day daily and Invirase 1000 mg/ritonavir 100 mg twice daily enrolled 28 healthy volunteers.

• Eleven of 17 (65%) healthy volunteers exposed concomitantly to rifampin and Invirase/ritonavir developed severe hepatocellular toxicity which presented as increased hepatic transaminases.
• In some subjects, transaminases increased up to > 20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting.
• Following discontinuation of all three drugs, clinical symptoms abated and hepatic transaminases normalized.

Additional Adverse Reactions Reported During Clinical Trials With Saquinavir

Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, thrombocytopenia

Cardiac disorders: heart murmur, syncope

Ear and labyrinth disorders: tinnitus

Eye disorders: visual impairment

Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitis

General disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy, wasting syndrome, weight increased

Hepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension

Immune system disorders: allergic reaction

Investigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline phosphatase, GGT increase, raised amylase, raised LDH

Metabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemia

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritis

Neoplasms benign, malignant and unspecified (including cysts and polyps): acute myeloid leukemia, papillomatosis

Nervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, tremor

Psychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, suicide attempt

Renal and urinary disorders: nephrolithiasis

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating increased, urticaria

Vascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction

Clinical Trial Experience In Pediatric Subjects

Limited safety data are available from two pediatric clinical trials of saquinavir mesylate capsules (hard gel) (approximately 50 mg per kg twice daily) used in combination with either low dose ritonavir or lopinavir/ritonavir.

These trials enrolled pediatric subjects aged 4 months to 16 years old. In the HIVNAT 017 study (saquinavir mesylate capsules (hard gel) + lopinavir/ritonavir), adverse events were reported in 90% of the 50 subjects enrolled.

The most commonly reported adverse events considered related to study treatment were diarrhea (18%) and vomiting (10%). In the NV20911 study (saquinavir mesylate capsules (hard gel) + ritonavir), 4 subjects (22% of 18 enrolled) experienced adverse events that were considered related to Invirase + ritonavir.

These events (n) were

• vomiting (3),
• abdominal pain (1) and
• diarrhea (1).

All reported adverse events were mild or moderate in intensity. The adverse reaction profile of Invirase in the pediatric trials is similar to that observed in adult trials.

Postmarketing Experience

Additional adverse events identified during postmarketing use are similar to those observed in clinical trials with Invirase, saquinavir mesylate capsules (hard gel and soft gel) alone or in combination with ritonavir.

Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Invirase exposure. In addition, torsade de pointes has been reported rarely.

Drug interaction studies have been completed with Invirase and saquinavir mesylate capsules (hard gel and soft gel). Observations from drug interaction studies with saquinavir mesylate capsules (soft gel) may not be predictive for Invirase/ritonavir.

Because ritonavir is coadministered with Invirase, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.

Potential For Invirase/Ritonavir To Affect Other Drugs

The combination Invirase/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A.

Drugs that are contraindicated specifically due to the observed or expected magnitude of interaction and potential for serious or life-threatening adverse events are listed in Section 4 Contraindications. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring (see Table 2).

Potential For Other Drugs To Affect Invirase/Ritonavir

The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is a substrate for P-glycoprotein (P-gp).

Therefore, drugs that affect CYP3A and/or P-gp may modify the pharmacokinetics of saquinavir.

Coadministration with drugs that are potent inducers of CYP3A (e.g., phenobarbital, phenytoin, carbamazepine) may result in decreased plasma concentrations of saquinavir and reduced therapeutic effect.

Established And Other Potentially Significant Drug Interactions

Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving Invirase/ritonavir, additive effects on QT and/or PR interval prolongation may occur with certain members of the following drug classes:

• antiarrhythmics class IA or class III,
• neuroleptics,
• antidepressants,
• PDE5 inhibitors (when used for pulmonary arterial hypertension),
• antimicrobials,
• antihistaminics and
• others.

This effect might lead to an increased risk of ventricular arrhythmias, notably torsade de pointes. Therefore, concurrent administration of these agents with Invirase/ritonavir is contraindicated.

Table 2 provides examples of established or potentially clinically significant drug interactions. This table includes potentially significant interactions but is not all inclusive. Alteration in dose or avoidance of the combination may be recommended depending on the interaction.

Table 2 : Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with Invirase/Ritonavir¹

Drugs Without Clinically Significant Interactions With Invirase/Ritonavir

Based on drug interaction studies conducted with Invirase/ritonavir, no clinically significant effect was observed for saquinavir when coadministered with fosamprenavir.

No clinically significant effect was observed for enfuvirtide when coadministered with Invirase/ritonavir.